The 5-(trifluoromethyl)pyrimidine derivatives and methods for producing the same according to the present invention have hitherto been unknown.
As for analogues of 2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine and 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to the present invention, 2-methoxy-4-chloro-5-(trifluoromethyl)pyrimidine has been known and there is a known method in which 2,4-dichloro-5-(trifluoromethyl)pyrimidine and methanol are reacted in the presence of triethylamine to give a mixture of 2-methoxy-4-chloro-5-(trifluoromethyl)pyrimidine and 2-chloro-4-methoxy-5-(trifluoromethyl)pyrimidine and the mixture is purified by silica gel column chromatography to obtain the intended 2-methoxy-4-chloro-5-(trifluoromethyl)pyrimidine (see Patent Document 1, for example).
However, there has been a problem in that when the method described in Patent Document 1 is used in an attempt to produce 2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine according to the present invention, the intended 2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine is not formed. There have also been problems in that: when the method is used in an attempt to produce 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine, the intended 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine is not formed; and with the use of a known method using a metal salt of an alcohol, in particular a method in which a lithium salt of benzyl alcohol and 2,4-dichloro-5-(trifluoromethyl)pyrimidine are reacted in a tetrahydrofuran solvent, the resulting product is a mixture of the intended 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine and its regioisomer, 2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine (intended product/isomer=73/27), and separation and purification by a process such as silica gel column chromatography must be performed to obtain the intended product.
On the other hand, as an analogue of 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine according to the present invention, 2,4-dichloro-5-(trifluoromethyl)pyrimidine (which may hereinafter be abbreviated as “CFP”) has been known and there is a known method in which the latter compound is substituted at the 2-position and 4-position of the pyrimidine ring by various substituents to produce candidate drugs for pharmaceuticals (see Patent Document 2, for example).
However, highly selective introduction of various substituents at the 2-position or 4-position with CFP is difficult by conventional methods, according to which the resulting product is a mixture of a 2-substituted product and a 4-substituted product. There has thus been a problem in that separation and purification by a process such as silica gel column chromatography must be performed to obtain the intended product of high purity.
Furthermore, as for an analogue of 2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine according to the present invention, 2-chloro-4-methylthio-5-(trifluoromethyl)pyrimidine has been known and is obtained by a reaction between 2,4-dichloro-5-(trifluoromethyl)pyrimidine and sodium thiomethoxide (see Patent Document 1, for example).
However, the method described in Patent Document 1 has problems in that it is a method involving purification by silica gel column chromatography of the mixture of 2-chloro-5-methylthio-5-(trifluoromethyl)pyrimidine and 2-methylthio-4-chloro-5-(trifluoromethyl)pyrimidine obtained by the reaction and is required to be further improved for use as an industrial production method, and in that the yield is 28%, which is low.